WO2024170654A1

WO2024170654A1 - An apparatus for releasing a drug

Info

Publication number: WO2024170654A1
Application number: PCT/EP2024/053779
Authority: WO
Inventors: Cristian Carlos D'ALESSANDRO
Original assignee: The Surgical Company International B.V.
Priority date: 2023-02-15
Filing date: 2024-02-14
Publication date: 2024-08-22
Also published as: NL2034151B1

Abstract

The present invention relates to an apparatus for releasing a drug and methods thereof. Said apparatus comprises: a heat exchanger unit comprising an inlet, an outlet, an internal fluid passageway connecting the inlet and the outlet, and a heat transfer surface configured to transfer heat to the internal fluid passageway; and a drug carrier capable of releasing a drug, wherein the drug carrier is in communication with the internal fluid passageway.

Description

An apparatus for releasing a drug

Field of the invention

The present invention relates to an apparatus suitable for releasing one or more drugs, particularly an apparatus that comprises a disposable heat exchanger unit for releasing said drugs. The present invention also extends to a method of making said apparatus, a method of operating said apparatus, and a method of preparing said apparatus for use.

Background to the invention

Controlled delivery of small, precise guantities of one or more medicines over a certain period is of great importance in the medical industry. Examples include delivery of intravenous fluid (IVF) via a thin tube (i.e. an IV line). In some cases, it is convenient or necessary to warm a fluid to a target temperature (e.g., to a body temperature of 36°C-37°C) before and/or during delivery to a patient. In the meantime, a different medicine (e.g. a prophylactic drug) may be administered, utilizing a number of different methods (e.g. oral, inhalation, instillation, injection, transdermal administration, rectal administration, vaginal administration). The drug is usually administered separately from the warm fluid, by using additional eguipment such as syringes, cartridges and disposable infusion bags. Generally considered to be different tasks, this separate administration increases the workload of the nurses and brings inconvenience to the patients. Further, the additional equipment is usually made from plastics or at least comprises plastics components. The equipment is suitably disposed after a single use to avoid contamination and/or infection. However, this increases wastes (e.g. plastics wastes), hence damaging our environment.

Further still, there remains a desire to improve the controlled delivery of drugs such that the dosage taken by the patient can have more uniform effect, and/or reduced fluctuation in circulating drug levels within the patient’s body.

It is in this context that the present invention has been devised. of the invention

In an aspect of the present invention, there is provided an apparatus for releasing a drug, comprising: (i) a heat exchanger unit comprising an inlet, an outlet, an internal fluid passageway connecting the inlet and the outlet, and a heat transfer surface configured to transfer heat to the internal fluid passageway, and (ii) a drug carrier capable of releasing a drug, wherein the drug carrier is in communication with the internal fluid passageway.

Typically, the internal fluid passageway is configured to allow a fluid (preferably an intravenous fluid) to flow through. It is understood that the internal fluid passageway normally does not contain a fluid. Thus, the fluid is not an essential feature of the apparatus. However, this does not exclude the possibility that the fluid passageway is loaded with a fluid (i.e. the apparatus optionally contains a fluid). The drug carrier is capable of being loaded with a drug. The drug carrier is capable of releasing the loaded drug. The drug carrier is in communication with (e.g. fluid communication with and/or thermal communication with) the internal fluid passageway. Typically, the internal fluid passageway is provided with the drug carrier. The internal fluid passageway is provided with the drug carrier such that when a fluid (e.g. an IVF) flows through the internal fluid passageway, said fluid causes a drug released from the drug carrier and/or the drug carrier to egress the heat exchanger unit via the outlet.

It may be that when the fluid flows through the passageway, said fluid is in fluid communication with the drug carrier and/or a drug released from said carrier. The fluid (e.g. the IV fluid) can be a medium into which the drug is released. The fluid (e.g. the IV fluid) and the drug may form a composition (e.g. a solution in which the drug is the solute and the fluid is the solvent). It may be that the fluid (e.g. the IV fluid) simply carries the drug to egress (e.g., leave, exit) the heat exchanger unit (e.g. as it flows through the outlet). The fluid (e.g. the IV fluid) and the drug carrier (e.g. the drug carrier loaded with the drug) may form a composition. It may be that the fluid (e.g. the IV fluid) carries the drug carrier (e.g. the drug carrier loaded with the drug) to egress the heat exchanger unit via the outlet. Thus, the fluid (preferably an IV fluid) and the drug can be delivered simultaneously by one apparatus to a patient. This reduces the inconvenience to the nurses and the patients. Further, this reduces the plastics wastes since no separate equipment is required to administer the drug. Comparing to some traditional administering methods such as an oral administration, the dosage of the drug is provided in a more continuous and more uniform manner to the patient. As such, it will be understood that the apparatus can be an apparatus for delivering a drug to a patient, preferably for delivering a drug and a fluid (e.g. IV fluid) simultaneously to a patient. It may be that the apparatus is configured to deliver a drug to a patient, preferably configured to deliver a drug and a fluid (e.g. IV fluid) simultaneously to a patient.

In the context of the present invention, examples of a fluid may include liquids and compositions (e.g. solutions). But typically, the fluid is not a gas, supercritical fluid, suspension, gel or paste. It is understood that an IV fluid (e.g a saline solution) is particularly preferred. However, this does not necessarily exclude other fluids (e.g. infusions, fluids that may be injected into tissues). The fluid may be blood plasma or (whole) blood. The invention (e.g. the apparatus) is mainly used in-vivo, but in-vitro is not excluded. As explained above, the fluid (e.g. the IV fluid) typically is not part of the apparatus (i.e. the apparatus does not contain said fluid) and the fluid (e.g. the IVF) is an optional feature of the invention. Since the drug may be delivered together with the fluid (e.g. the IV fluid), the invention provides fine control over the amount of the drug delivered as well as the time and rate at which delivery occurs.

The fluid passageway is an internal fluid passageway, meaning that said passageway is contained within the heat exchanger unit. Typically, the heat exchanger unit provides at least one surface (e.g. one internal surface) to define said passageway. This contrasts with arrangements in which the heat exchanger unit may be a torus or in toroidal shape with a through opening in the middle to allow passing of the fluid (e.g. an external fluid passageway). Such an external fluid passageway is normally defined by one or more external surfaces of the relevant unit. The internal passageway has the advantage of keeping its contents (e.g. the drug carrier, the fluid) warm in comparison to the external passageway, as well as other advantages such as protecting its contents from physical and/or chemical damages. The shape, size, and other aspects of the internal fluid passageway may vary. Said passageway may be in a polyhedron shape (e.g. a rectangular prism), or a non-polyhedron shape (e.g. a cylinder), both of which is easy to design and simple to manufacture. Said passageway may be in a serpentine shape, which maximises the efficiency of the heat transfer as well as reduces the fluctuation of the heat within the passageway (e.g. by avoiding hot spots of high temperatures). Preferably said passageway within the heat exchanger unit is substantially planar, or otherwise shaped to maximise the heat transfer via the heat transfer surface.

Typically, the heat exchanger unit is a disposable unit (e.g., disposable after a single use). Typically, the heat exchanger unit is configured for a single use, optionally for up to 24 hours, or up to 12 hours, or up to 6 hours. The design and the material of the heat exchanger unit may vary. The heat exchanger unit may be a simple fluid conduit, such as a tube or similar, or it may be a cassette, or any other structure having the internal fluid passageway operably in thermal contact with a heater unit via the heat transfer surface. It may be that the internal fluid passageway is in thermal communication with the heat transfer surface. It may be that the drug carrier is in thermal communication with the heat transfer surface. It may be that the drug is in thermal communication with the heat transfer surface. It may be that the internal fluid passageway is in thermal contact with the heater unit via the heat transfer surface. It may be that the drug carrier is in thermal contact with the heater unit via the heat transfer surface. It may be that the drug is in thermal contact with the heater unit via the heat transfer surface.

The heat exchanger unit provides an inlet and an outlet (e.g. through which a fluid can pass). The heat exchanger unit comprises a heat transfer surface, which is typically for transferring heat between the heater unit and the internal fluid passing between the inlet and the outlet of the heat exchanger unit. Typically, the heat transfer surface is also for transferring heat to the drug carrier comprised in the heat exchanging unit. It may be that the heat transfer surface is configured to transfer heat to the drug carrier. Thus, the apparatus may be configured to warm the fluid, and/or the drug carrier, and/or the drug. The apparatus may be configured to deliver the warm fluid, and/or the warm drug carrier, and/or the warm drug to the patient. It may be that the heat transfer to the internal fluid passageway, and/or the drug carrier, and/or the drug is operably effected via the heat transfer surface. The heat exchanger unit may comprise a layer comprising the heat transfer surface. Said layer may comprise (e.g. be) heat conductive material. Said layer may comprise plastics, and/or metal. Said layer may comprise aluminium, and/or parylene. It is understood that the heat transfer surface may be formed by any one or combination of these above-described materials. The heat exchanger unit may comprise one or more further layers in addition to the layer comprising the heat transfer surface. The heat exchanger unit may comprise a first parylene layer comprising the heat transfer surface, an aluminium layer (e.g., to provide structure stiffness), and a second parylene layer, wherein the first parylene layer is provided with an aluminium layer and the aluminium layer is provided with the second parylene layer, in turn. The heat exchanger unit may comprise alternating layers of parylene and aluminium.

It may be that the heat exchanger unit is connected or connectable to a fluid conduit via the inlet and the outlet, for transferring the fluid to or from the internal fluid passageway. One end of the fluid conduit may be configured to permit an IV injection (e.g., via a needle). The apparatus may be an apparatus for delivering a fluid and a drug simultaneously to a patient. Preferably the surface area per length of the internal fluid passageway within the heat exchanger unit is larger than that of the conduit (outside the heat exchanger unit), and more preferably the surface area per unit length on the side of the internal fluid passageway operably facing the heater unit is larger than that of the conduit (outside the heat exchanger unit). These arrangements increase heat transfer efficiency as well as reduce heat loss during delivery to a patient.

It may be that the apparatus further comprises a heating unit configured to heat the heat exchanger unit via the heat transfer surface. It may be that the heat exchanger unit is removably attachable to the heating unit. When attached, the heat transfer from the heating unit to the heat exchanger unit is effected via the heat transfer surface. The heating unit is an optional feature of the present invention, since the heat may come from natural heat (e.g. the sun). The exchanger unit may be placed in a hot room, with sufficient sunlight and/or with air conditioning. But the heating unit provides a more efficient and controlled way to heat the heat exchanger unit. The present invention may also provide the benefit of delivering warm fluid (e.g. warm IV fluid) and warm drug to a patient concurrently. The apparatus may be an apparatus for warming the fluid. The apparatus may be an apparatus for warming the drug and/or the drug carrier. The apparatus may be suitable for warming the fluid (e.g., the IV fluid), the drug and/or the drug carrier simultaneously. Suitably, the apparatus may comprise a plurality of heat exchanger units. The drug carrier may be comprised in a first heat exchanger unit which is a disposable unit (preferably made from plastics, preferably a plastics cassette). The apparatus may comprise a second heat exchanger unit, wherein the first heat exchanger unit is removably attachable to the second heat exchanger unit. The second heat exchanger unit may be removably attachable to a heating unit. Both heat exchanger units may comprise a heat transfer surface. The first heat exchanger unit may comprise the outlet, the inlet, the passageway, as described herein.

The heating unit may be configured to heat the heat exchanger unit (e.g. the fluid, the drug carrier and/or the drug) to a temperature of from 25°C to 60°C, or from 30°C to 50°C, or from 35°C to 40°C (e.g. 36-37°C). The heat exchanger unit may be configured to maintain any of the said temperatures. The heating unit may comprise one or more heating elements. The heating element may be an electrical heating element (i.e. the heating unit is an electrical heater). A suitable example of such a heating unit and its component parts is as described in US 9895498B2 in which the heater unit is equivalent to the heating unit as described herein. The heating unit is typically electrically isolated from the heat exchanger unit. The heating element may be an electroluminescent radiation source (e.g. infrared radiation source). Correspondingly, the heat transfer surface is suitable for transferring electroluminescent radiation (e.g. infrared (IR) radiation). The heat exchanger unit may be configured to absorb electroluminescent radiation (e.g. IR radiation). The heating unit may be configured to illuminate the heat exchanger unit by electroluminescent radiation (e.g. IR radiation). The apparatus that comprises an electroluminescent radiation source to warm the fluid (as well as the drug carrier and/or the drug) is contemplated. Such an apparatus and its component parts (e.g. controller, fluid conduit) may be suitably as described in EP35428441A1. The fluid conduit may be provided with the drug carrier.

The heating unit may comprise one or more temperature sensors. The apparatus may further comprise a controller. The controller may be programmed to receive the temperature measurement from the temperature sensor, process said temperature measurement to determine a temperature difference between the inlet and the outlet of the heat exchanger unit, compute a fluid flow rate corresponding to the rate of flow of the fluid from the inlet to the outlet, and control the power supplied to the heating element. Alternatively or additionally, the controller may be programmed to control the flow rate of the fluid (e.g. the IV fluid), and/or the flow rate of the drug carrier, and/or the flow rate of the one or more drugs. Thus, the controller may be programmed to control the dosage of the fluid (e.g. the IV fluid) delivered to a patient, and/or the dosage of the drug carrier, and/or the dosage of the drug. Such a controller, the relevant heating unit, and the heat exchanger unit contemplated may be as described in US 10722660B2. Further, suitable examples contemplated for a heating unit (e.g. a heater), a controller, a temperature sensor may be as described by EP 3266 426 B1.

It will be understood that the materials and designs of the heat exchanger unit and the heater unit are selected so as to allow efficient heat transfer and to allow delivery of the warm fluid and drug simultaneously to a patient. The skilled person may select suitable heat exchanger unit (excluding the drug carrier, the bonding and the drug which will be described hereinafter) and heating unit in accordance with the disclosures of US 9895498B2, EP35428441A1, US 10722660B2 and EP 3266 426 B1 , all of which are incorporated herein by reference. The heating units (including any component parts of the heating units) described by those documents may be suitably used for the present invention. The heat exchanger units (including any component parts of said units) described by those documents may be suitably used for the present invention. The heating units and the heat exchanger units, wherever disclosed together by any of those documents, may also be suitably applied together in the context of the present invention.

Preferably, the fluid refers to an IV fluid. Herein, the IV fluid should be understood broadly to mean a fluid given intravenously. It may be a substance but typically a composition. For example, it may be blood (e.g. whole blood), blood plasma, crystalloid solutions (e.g. saline, dextrose in water, sodium lactate solution), and colloids (e.g. albumin, hetastarch). The IV fluid may be a blood (e.g. whole blood), blood plasma, or a saline. The IV fluid may be a saline. The IV fluid may be given to a patient over a certain period of time for single or multiple purposes (e.g. therapeutic, diagnostic). The IV fluid may be understood as an infusate. The IV fluid can be a medium into which the drug is released. The IV fluid may operably carry the drug to egress via the outlet of the heat exchanger unit. The IV fluid may operably carry the drug carrier (e.g. the drug carrier loaded with the drug) to egress via the outlet of the heat exchanger unit. Thus, the drug may be conveniently delivered together with the IV fluid, increasing the continuity and uniformity of the drug delivery. It may be that the heat exchanger unit provides at least one surface (e.g. at least one internal surface) defining the internal fluid passageway. It may be that the drug carrier is bonded to the at least one surface of the internal fluid passageway. It may be that the drug carrier is directly or indirectly (e.g. via a linker) bonded to the surface. Herein, ‘bonded to’ may refer to any of ‘attached to, adhered to, joined to, integrated to, connected to, fixed to, affixed to, secured to, bound to, and coupled to’. Bonding allows the drug carrier to be in a relatively fixed position within the heat exchanger unit at least during transporting the apparatus, and/or preparing the apparatus for use. This reduces accidental damages to the drug carrier before drug release. Additionally and optionally, the drug carrier remains (e.g. is) bonded to the at least one surface when the fluid (e.g. the IV fluid) flows through the internal fluid passageway. The drug carrier may be bonded to the at least one surface when releasing a drug into the passing fluid. This allows better control of the drug release and further ensures the uniformity as well as the time and rate of the drug delivery.

It may be that the drug carrier is reversibly bonded to the surface. This allows at least part of if not substantially all of the drug carrier(s) to be released together with the loaded drug(s) from the at least one surface. The drug carrier may be designed to be operably releasable from the at least one surface. The drug carrier may be designed to be released from said surface by one or more of the following factors: heat, light, magnetism, sound, pH, ionic strength, hydrolysis, enzymes, IV fluid, osmosis, diffusion, elution and humidity. Preferably, the drug carrier is designed to be released from the at least one surface by heat, and/or by infusate (e.g. blood, blood plasma, saline). It is understood that the drug carrier may optionally not be bonded to the at least one surface (e.g. the internal fluid passageway can simply be provided with the drug carrier). If not bonded, it is also possible that the drug carrier (e.g. the drug carrier loaded with a drug) egresses the heat exchanger unit via the outlet due to the presence of heat (e.g. heat flow) and/or infusate (e.g. infusate flow). Any of the above-described factors or combination of factors may also suitably apply. Thus, during use, when the heater exchanger unit is heated up and/or provided with an IV fluid, the drug carrier may be released from the at least one surface (and/or simply allow to exit the heat exchanger unit), and carry the loaded drug into the patient’s body. The drug carrier may be designed for target delivery. By ‘target delivery’ we mean that the drug carrier is designed to carry the drug to a desired part of the body that requires the treatment, thereby increasing the concentration of the drug in said part relative to other parts. This may reduce the overall dosage needed by the patient and in the meantime, improve the effectiveness of the treatment.

The carrier can be mechanically, physically, biologically, and/or chemically bonded to the surface. By way of example, a layer comprising a drug carrier may be attached to (e.g. mechanically affixed to) the at least one surface of the fluid passageway. Said layer may be coated on said surface (e.g by mechanical or any suitable means). By way of further example, the drug carrier may be bonded by physical adsorption. The drug carrier may be chemically bonded to the surface of the internal fluid passageway. Herein, the chemical bond can include but is not limited to a covalent bond, a non- covalent bond (e.g., an ionic bond), a metallic bond, a hydrogen bond, a chelated bond, those non-covalent interactions such as van der Waals force, TT-TT interaction, hydrophobic or hydrophilic effect, electrostatic interaction, polymer wrapping, grafting (e.g. photo grafting) and combinations thereof. For example, the at least one surface of the passageway may comprise (e.g. be) aluminium. The drug carrier may be a nano- porous alumina. Thus, the drug carrier may be bonded to the surface by metallic bonding. It may be that the drug carrier is bonded to the at least one surface by an adhesive. It may be that the drug carrier is adhered to the at least one surface (e.g. by an adhesive).

It may be that a layer is bonded to (e.g. adhered to) the at least one surface and said layer comprises (e.g. is formed of) one or more drug carriers. The thickness of the layer may be from 1 nm to 1000pm, or from 10nm to 100 pm, or from 20 nm to 10 pm, or from 30nm to 1 pm, or from 50nm to 100nm. The layered structure and/or the suggested thickness may provide enhanced efficiency of the release of the drug and/or drug carrier.

At least 5% of the total surface area of the internal fluid passageway may be covered by the drug carrier, or at least 10%, or at least 20%, or at least 50%, or at least 70%, or at least 90%. The high percentage of coverage maximises the release of the drug and/or drug carrier.

It may be that the drug carrier (e.g. the layer comprising the drug carrier) is disposed adjacent to the heat transfer surface. It may be that the heat transfer surface is at least part of the external surface of a side of the heat exchanger unit and the drug carrier (e.g. the layer comprising the drug carrier) is disposed on the internal surface of the same side of the heat exchanger unit. Said internal surface may define (at least part of) the internal fluid passageway. The heat transfer surface may define (at least part of) the internal fluid passageway. The drug carrier may be bonded (as described herein) to said internal surface. The drug carrier may be bonded (as described herein) to the internal fluid passageway. The heat exchanger unit may comprise a layer comprising the heat transfer surface and optionally, the heat transfer surface may be formed by parylene and/or aluminium. It may be that the heat transfer surface is in thermal communication with the drug carrier to transfer heat to said drug carrier. It may be that the heat transfer surface is in thermal communication with the internal fluid passageway to transfer heat to the fluid passing through said passageway. It may be that the internal fluid passageway is provided with the drug carrier. It may be that the drug carrier and the internal fluid passageway are in thermal communication (and fluid communication). It may be that the heat transfer surface is configured to transfer heat to the internal fluid passageway so as to heat the drug carrier. It may be that heat is (operably) transferred to the internal fluid passageway via the heat transfer surface to thereby heat the drug carrier (and the fluid passing through the internal fluid passageway).

It may be that the heat exchanger unit comprises a first parylene layer comprising the heat transfer surface, an aluminium layer, and a second parylene layer, wherein the first parylene layer is provided with the aluminium layer, the aluminium layer is provided with the second parylene layer, and the second parylene layer is provided with the drug carrier. A surface of the second parylene layer may define (at least part of) the internal fluid passageway. It may be that the drug carrier is bonded to said surface of the second parylene layer. It may be that the drug carrier is bonded to said surface of the second parylene layer such that it is also bonded to the internal fluid passageway. The drug carrier may be bonded mechanically, physically, biologically, and/or chemically (e.g. via adhesion, via linker), as described herein. It will be understood that the drug carrier is different from the parylene layer(s) and the aluminium layer.

The above arrangement increases the heat transfer to the drug carrier, thereby enhancing the release of the drug and/or drug carrier (for example, if the drug carrier is heat sensitive). The arrangement may also efficiently warm up the drug and drug carrier. When the fluid (e.g. IV fluid) passes through the internal fluid passageway, the fluid may also be efficiently warmed. Thus, this arrangement may concurrently heat the drug carrier and the fluid in an efficient manner. It may be that the drug carrier is bonded to the at least one surface of the internal fluid passageway via adhesion. It may be that the drug carrier is adhered to the at least one surface. The adhesion may be reversible adhesion, meaning that the drug carrier is reversibly bonded to the at least one surface as described previously. The adhesion may be achieved by chemistry, topology, mechanics, or combinations thereof. Suitably, the adhesion is achieved by chemical bond (e.g. the chemical bond as described previously), polymer chain, polymer crosslink, polymer network, nanoparticle, direct wafer bond, cold weld, diffusion bond, surface modification, topological adhesion, physical entanglement, mechanical interlock, adhesive bond, or combinations thereof, more suitably by chemical bond (e.g. the chemical bond as described previously), polymer chain, polymer crosslink, polymer network, surface modification, topological adhesion, physical entanglement, mechanical interlock, adhesive bond, or combinations thereof. Suitably, the drug carrier is bonded to (e.g. adhered to) the at least one surface by one or more of the following operations: casting, coating, printing, attaching, piercing, and gluing. It may be that the drug carrier is bonded to (e.g. adhered to) the at least one surface by an adhesive.

It may be that the drug carrier is bonded to (e.g. adhered to) the at least one surface of the internal fluid passageway via a linker, for example an adhesive linker. Suitably, the linker is selected from nanoparticles, polymers, polymer brushes, surfactants, lipids, hydrocarbon chains, ligands, metals, metal oxides, natural adhesives, synthetic adhesives, and mixtures thereof.

Adhesive linker is preferred since this provides a simple way to bond a drug carrier. In other words, the drug carrier can be adhered to the surface of the internal passageway by a simple and effective action. The adhesive linker may be applied to the drug carrier (e.g. a layer comprising the drug carrier) or the surface of the internal fluid passageway or both. The adhesive linker may be incorporated into or associated with the drug carrier (e.g. a layer comprising the drug carrier), or said surface or both. A skilled person may choose any suitable adhesive linker such as a polymer. Adhesive linker may comprise (e.g. be) one or more of the followings: resin, epoxy resin, cyanoacrylate, (meth)acrylate, elastomer (e.g. styrene-isoprene-styrene triblock copolymer), polyvinyl, polyvinyl acetate, polyvinyl alkyl ether, polyethylene, polypropylene, ethylene propylene copolymer, polyamide, polyester, vinyl acetateethylene copolymer, synthetic rubber, natural rubber, polyurethane, neoprene, silicone, wax, collagen, casein, albumen, starch, dextrin, agar, algin, gum Arabic, latex and cellulose.

The linker molecule may be compatible (e.g. biocompatible) with the surface of the passageway, and/or the drug carrier. It is understood that the skilled person may choose the suitable linker according to the material of the passageway, and/or the material of the drug carrier. It may be that the linker permits temporary bonding of the drug carrier (i.e. a reverse bonding meaning the bonded drug carrier can be released from the at least one surface of the passageway during operation, as described hereinbefore). The linker may be designed to release the drug carrier loaded with the drug once the linker is activated. The linker may be a (e.g. selectively) cleavable linker. The linker may be activated to release the drug carrier (from the at least one surface) by any suitable means (e.g. heat, UV, Infrared radiation, pH, pressure, ultrasound, ionic strength, hydrolysis, enzymes, intravenous fluid, osmosis, diffusion, elution, humidity). A skilled person may choose an appropriate linker. For example, a heat sensitive linker (e.g. thermoplastic resins, polyamides, polyesters, ethylene-vinyl acetates, polyurethanes, elastomers, butyl rubbers, styrene-butadiene rubbers, ethylene-propylene copolymers) may be used (e.g. for temporary bonding). When the heat exchanger unit is warmed up the linker may be degraded or partially degraded to release the drug carrier. This allows the carrier with the loaded drug to enter the patient’s body, and the carrier may release the drug at the desired part of the body to provide an effective treatment. In other words, this enables a target delivery of the drug.

The drug carrier typically comprises (e.g. is) a substrate, capable of being loaded with one or more drugs. The use of drug carrier may improve one or more aspects of the drug delivery such as safety, selectivity, effectiveness, controlled release and bioavailability of the drugs. In the context of the present invention, the drug carrier is capable of releasing a drug (e.g. into the internal fluid passageway, or at the location of the patient’s body where treatment is needed). Typically, the drug carrier is designed to release a drug into the internal fluid passageway. Typically, the drug carrier is biodegradable. Typically, the drug carrier is biocompatible with the fluid (e.g., the IV fluid), the surface of the passageway and the drug perse. It will be understood that the drug carrier is different from the fluid (e.g. different from the IV fluid). Typically, the drug carrier is sterilised, to improve the hygiene of the apparatus. It may be that the drug carrier is selected from hydrogels, lamellae, membranes, vesicles, micelles, bilayers, liposomes, capsules, dendrimers, polymers, microspheres, matrices, filaments, quantum dots, nanostructures, and mixtures thereof, preferably selected from hydrogels, nanostructures and mixtures thereof. Nanostructure is preferred since this size is efficient, practical as well as convenient for target drug delivery. Preferably, the nanostructure is porous. A porous nanostructure is well suited to drug loading as well as drug release. A nanostructure preferably a porous nanostructure may be selected from nanofibers, nanowires, nanotubes, nanoparticles, and combinations thereof. It may be that the drug carrier is a nanostructure (as described herein) comprised in a layer bonded to the at least one surface of the fluid passageway. It may be that the heat exchanger unit comprises one or more woven and nonwoven fibrous mats bonded to (e.g. adhered to) the at least one surface of the fluid passageway, wherein said mat comprises a drug carrier which is a structure (e.g. a nanostructure), as described herein.

Hydrogels are also preferred since they share a lot of similarities with bodily soft tissues such as skin, mucosa and blood vessels, and are mostly biocompatible with these tissues. The hydrogel typically comprises at least 60% water by weight of the total hydrogel excluding any loaded drugs, or at least 80 wt%, or at least 90wt%, or at least 95wt%. The hydrogel typically comprises a hydrophilic polymer, optionally selected from non-ionic, anionic, cationic and zwitterionic natural hydrophilic biopolymers, synthetic hydrophilic polymers, hydrocolloids, gelling hydrophilic biopolymers and combinations thereof. The hydrophilic polymer typically comprises one or more of the following groups: hydroxyl, carboxyl, carboxamido, and ester. Suitable hydrophilic polymers include but are not limited to gelatine, poly(vinyl alcohol), poly(hydroxy alkyl methacrylate), poly(ethylenimine), polyethylene-polypropylene copolymers, alginate, collagen, chitosan, polysaccharides, crosslinked acrylamide polymers, thermoplastic polyurethanes (TPUs), crosslinked acrylates or methacrylates, crosslinked polymers and copolymers of N-vinylpyrrolidinone and crosslinked polymers and copolymers of acrylic acid. The hydrophilic polymer or polymers typically present a cross-linked polymer network. The network is well suited to encapsulating hydrophilic drugs and providing protection to minimise drug denaturation. The hydrogels may be macroscopic hydrogels, micro hydrogels, or nano hydrogels. Herein, the term “hydrogel” is not to be considered as limited to gels that contain water, but extend generally to all hydrophilic gels, including those containing organic non-polymeric components. Suitably hydrogels are also described in greater detail in Hydrogels, Kirk-Othmer Encyclopaedia of Chemical Technology, 4^th Edition, vol. 7, pages 783-807, John Wiley and Sons, New York, the contents of which are incorporated herein by reference. Suitably hydrogels as drug carriers for drug delivery are specially described in designing hydrogels for controller drug delivery, Nat Rev Mater. 2016 December; 1(12) by Jianyu Li and David J. Mooney, the content of which is incorporated herein by reference.

It may be that the nanostructures and/or the hydrogels are bonded to (e.g. adhered to) the at least one surface, as described herein. It may be that the nanostructure and/or the hydrogel is sticky such that it is suitable for adhering to said at least one surface. It may be that the nanostructures and/or the hydrogels are bonded to said surface by an adhesive.

It may be that the drug carrier is a nanostructure (as described herein) comprising one or more of the followings: polyvinyl alcohol, polytetrafluoroethylene, polylactic acid (e.g. poly-L-lactic acid), polyethylene glycol, poly(lactic-co-glycolic acid), poly(caprolactone), synthetic polymers, hydrophilic polymers, peptides, poly(dicyclopentadiene), alginate, chitosan, chitin, glycosaminoglycans, hyaluronic acid, collagen, gellan gum, starch, guar gum, gum Arabic, galactans, carrageenan, Xanthan gum, cellulose, hydroxyapatite, silicone, gluconate, sucrose, dextran, octocalciumphosphate, dicyclopentadiene, nanoporous anodic alumina, and polyelectrolyte. The drug carrier may be a porous nanostructure comprising one or more of the above-mentioned materials. Additionally or alternatively, the drug carrier may be a hydrogel comprising one or more of the above-mentioned materials. Suitably, the drug carrier may be selected from hydrogels, nanostructures, and mixtures thereof, wherein the nanostructures comprise nanoporous anodic alumina.

The drug carrier may be a synthetic, biodegradable carrier, wherein optionally the drug carrier comprises one or more of the followings: poly(amides) such as poly(amino acids) and poly(peptides), poly (esters) such as poly(lactic acid), poly(glycolic acid), poly (lactic-co-glycolic acid), poly(caprolactone), poly (anhydrides), poly(ortho- esters), and poly(carbonates). The drug carrier may be a (porous) nanostructure comprising one or more of the above-mentioned materials. Additionally or alternatively, the drug carrier may be a hydrogel comprising one or more of the above-mentioned materials.

The drug carrier may be a synthetic, non-biodegradable carrier, wherein optionally the drug carrier comprises one or more of the followings: poly(ethers) such as poly(ethylene oxide), poly(ethylene glycol), and poly(tetramethylene oxide), vinyl polymers, poly(acrylates) and poly(methacrylates) such as methyl, ethyl, other alkyl, hydroxyethyl methacrylate, acrylic and methacrylic acids, and others such as poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate), poly(urethanes), cellulose and its derivatives such as alkyl, hydroxy alkyl, ethers, esters, nitrocellulose, and cellulose acetates, and poly(siloxanes). The drug carrier may be a (porous) nanostructure comprising one or more of the above-mentioned materials. Additionally or alternatively, the drug carrier may be a hydrogel comprising one or more of the above- mentioned materials.

It may be that the drug carrier comprises one or more of the followings: poly-(d,l- lactide), poly-(d-lactide), poly-(l-lactide), poly(d,l-lactic acid), poly(l-lactic acid), poly(d- lactic acid), ethylene vinyl alcohol (EVOH), e-caprolactone, ethylvinyl hydroxylated acetate (EVA), polyvinyl alcohol (PVA), polyethylene oxides (PEO), polyvinyl alcohol, polytetrafluoroethylene, poly(dicyclopentadiene), poly(caprolactone), hydrophilic polymers, and poly(lactic-co-glycolic acid).

Mixtures of any of the above-described materials may also be used.

It may be that the drug carrier comprises nanoporous anodic alumina (NAA). NAA may be obtained by simple fabrication and its pore size and depth can be controlled by regulating the anodizing voltage, time and electrolyte composition. Depending on the fabrication techniques, NNA may also provide high surface area and highly ordered pore structure within which a drug can be loaded. This may result in favourable pharmacokinetics. The NAA may comprise a plurality of nano-concavities. The NAA may comprise a porous layer comprising said nano-concavities. These structures are obtainable by electropolishing. Conveniently, NAA is configured to be loaded with a drug or a further drug carrier, optionally in the nanopores (e.g. nano-concavities). It may be that the nanopores (e.g. nano-concavities) are configured to be loaded with a drug or a further drug carrier. The NAA may be bonded to the at least one surface (e.g. via a linker such as an adhesive linker). The NAA may be bonded to the at least one surface by metallic bonding or other suitable interactions.

It may be that the drug carrier comprising nanoporous anodic alumina is a first drug carrier, the apparatus further comprises a second drug carrier which comprises one or more electrolytes in the form of multilayers, and the first drug carrier is provided with the second drug carrier. The second drug carrier may be configured to be loaded with a drug (e.g. doxorubicin). The use of a second drug carrier is advantageous because the drug release may be triggered by simple chemical means such as pH and/or ionic strength. For instance, the IV fluid with appropriate pH and/or ionic strength may trigger the multilayer electrolyte to release the loaded drug. The second drug carrier may comprise poly(styrenesulfonate), and/or poly(allylamine hydrochloride). The second drug carrier may be bonded to the first drug carrier by electrostatic interaction. The first drug carrier may be loaded with the second drug carrier. For instance, the nanopores (e.g. nano-concavities) of the NAA may be loaded with the second drug carrier (e.g. the one or more electrolytes in the form of multilayers).

It may be that the drug carrier is designed to be activated to release a drug by one or more of the following factors: light, sound, heat, magnetism, pH, ionic strength, hydrolysis, enzymes, intravenous fluid, osmosis, diffusion, elution, humidity, preferably by heat and/or by intravenous fluid. The light may be UV light, or infrared. The sound may be ultrasound. The skilled worker may select suitable material to make the drug carrier according to the activation factor, versa vice (e.g. a UV polymerised polymer that is sensitive to heat or an IV fluid).

Heat is a preferred way because a heat sensitive drug carrier may be conveniently warmed up (e.g. when the IV fluid is warmed up). The presence of heat (e.g. heat flow) may be due to the heat transfer to the internal fluid passageway via the heat transfer surface. The carrier may lose its structural integrity (e.g. due to melting under heat) to release the drug. Several purposes may be achieved simultaneously by transferring heat to the internal fluid passageway, including warming the IV fluid, releasing the drug, warming the drug and facilitating dissolution of the drug into the IV fluid.

The IV fluid is another preferred way since this simplifies the procedure of drug releasing without involving additional energy. The IV fluid is typically (whole)blood, blood plasma, or saline. The IV fluid may be simply loaded into the internal fluid passageway. The drug carrier may be porous. The drug carrier may be a porous nanostructure. The porous structure allows the loaded drug to be eluted by the fluid (e.g. by the IV fluid). The drug may also diffuse out of the porous structure. The drug carrier may dissolve upon contacting the IV fluid to release the drug. The drug carrier may be soluble in the fluid especially IV fluid. The term ‘soluble’ is used with reference to the solubility of a solute (e.g. the drug carrier) in the solvent (e.g. the fluid especially the IV fluid). It should be understood to mean that the solute (e.g. drug carrier) has a solubility in the solvent (e.g. fluid especially IV fluid) of greater than 0.1g/100mL, or greater than 1g/100mL, or greater than 10g/100mL, all measured at an elevated temperature. An ‘elevated’ temperature is typically 36-37°C. An ‘elevated’ temperature may also be a temperature of from 25°C to 50°C, or from 30°C to 45°C, or from 35°C to 40°C. It will also be understood that the drug carrier may be insoluble in the fluid especially the IV fluid (e.g. for target drug delivery). ‘Insoluble’ means at the elevated temperature, the solubility is typically no greater than 0.1g/100mL, or no greater than 0.01g/100mL, or no greater than 0.001g/100mL.

It may be that the drug carrier is designed to release the drug actively or passively. Passive release can be fabricated by using materials that allow the drug molecules to diffuse passively out of the carrier over time. Active release can be fabricated by using materials that disintegrate upon application of various of factors including thermal energy (e.g. heat and/or IR radiation as described above).

The drug carrier may be designed to release the drug in a pulsatile manner. This may prevent the drug concentration in a patient’s body falling below a desired level. The drug carrier may be designed to release the drug in a continuous manner. This may prevent or reduce the drug level from fluctuating in a patient’s body. The drug carrier may be designed to release a drug over a period of time, for example, from 10 minutes to 10 hours, or from 20 minutes to 5 hours, or from 40 minutes to 2 hours. These periods are substantially the same as those over which a patient may receive an IV fluid. Thus, the patient may receive two treatments simultaneously without prolonging the treatment time.

It may be that the drug carrier is loaded with a drug. The drug is a preferred feature of the present invention but not essential. Typically, the drug is different from the IV fluid. Typically, the drug is different from the drug carrier. It may be that the apparatus comprises a plurality of drug carriers. It may be that at least one of or all of the drug carriers are loaded with a drug. It may be that the apparatus comprises a first drug carrier and a second drug carrier, and a first drug carrier is provided with a second drug carrier. It may be that the second drug carrier is loaded with a drug.

‘Loaded with’ may refer to ‘encapsulated within’. Typically, the drug carrier is a shell (i.e. a capsule), the drug is a core encapsulated within the shell, and the drug and the drug carrier form an encapsulation. But this does not exclude other ways of loading the drug. For example, the drug may be attached to the drug carrier by chemical and/or physical interactions (e.g. adsorption). It may be that the drug is loaded into the nanotube as a drug carrier. It may be that the drug is loaded into the nanopores of a nano-porous drug carrier. It may be that the drug is loaded into the hydrogel as a drug carrier.

The drug is typically suitable to be delivered to a patient intravenously. Thus, the drug may be delivered simultaneously with an IV fluid to a patient. This in general helps to increase convenience for the patients and the nurses, reduce the number of equipment involved (e.g. reducing the amount of plastics used), and improve the drug delivery in terms of uniformity and continuity.

The drug is typically compatible (e.g. biocompatible) with the fluid. ‘Compatible’ should be understood to mean the drug and fluid, when administered simultaneously, do not cause an adverse effect to a patient. If a side effected is predicted, this may be prevented or mitigated by means such as drug encapsulation. It may be that when delivered together, the drug does not interact with the fluid (e.g. the IV fluid) to produce a side effect or to reduce the performance of the drug itself or the fluid. It may be that when delivered together, the drug is capable of an interaction with the fluid (e.g. the IV fluid) to enhance the performance of the fluid and/or the drug, and/or to reduce an adverse effect. A skilled person may select the appropriate drug in view of the fluid (e.g. the IV fluid) in use. By way of example, a skilled person may not select a calcium- rich drug if blood is the IV fluid. By way of further example, a heparin may be selected for an IV fluid (e.g. blood) for its anti-coagulation property.

The drug may be selected from natural dugs, synthetic drugs, organic drugs, inorganic drugs, and mixtures thereof. The drug may be selected from therapeutic drugs, prophylactic drugs, diagnostic drugs, and mixtures thereof. The drug may comprise one or more selected from the group of (e.g. the group consisting of): antibiotics (e.g. doxorubicin), chemotherapeutic agents, anti-allergens, anti-cholinergic agents, antihistamines, anti-platelet agents, anti-coagulants, decongestants, healing promoting agents, hyperosmolar agents, anti-scarring agents, in vivo diagnostic agents (e.g., contrast agents), sugars, vitamins, minerals (e.g. calcium), anti-inflammatory agents, painkillers (e.g. opioids), medications useful for renal procedures such as dialysis (e.g., heparin), pH buffering agents, anti-restenosis compounds, antithrombotic, anti-neoplastics, anti-proliferative agents (e.g. taxol), anti-sense compounds, anti-infective agents, tissue growth stimulants, tissue adsorption enhancers, proteins (e.g. proteoglycans), nucleic acids (e.g. polynucleotides), polysaccharides, synthetic organic molecules having a bioactive effect, anaesthetics, muscle relaxant (e.g. rocuronium), vaccines, hormones, metabolites, immunomodulators, immunosuppressive agents(e.g. macrocyclic triene immunosuppressive compounds), antioxidants, and ion channel regulators. The drug can be in the form of a single drug or drug mixtures. The drug can be a substance or a composition. It may be that the drug includes pharmaceutically acceptable carriers.

The drug may be selected from (e.g. selected from the group consisting of): antibiotics, heparin, opioids, rocuronium, calcium, taxol, proteoglycans, polynucleotides, macrocyclic triene immunosuppressive compounds, dexamethasone, M-prednisolone, interferon, leflunomide, tacrolimus, statins, cyclosporine, methotrexate, actinomycin, angiopeptin, vincristine, mitomycin, ribozyme, batimastat, halofuginone, C-proteinase, inhibitors, probucol, estradiols, and mixtures thereof. Preferably, the drug is selected from heparin, antibiotics, opioids, rocuronium, calcium and mixtures thereof. Typically, the drug is compatible (e.g. biocompatible) with the fluid (e.g. the IV fluid) used. Typically, the drug comprises (e.g. is) heparin if the fluid comprises (e.g. is) blood, or blood plasma. Typically, the drug is selected from antibiotics, opioids, rocuronium, calcium and mixtures thereof, if the fluid comprises (e.g. is) saline.

The drug may be a cancer drug, selected from monoclonal antibodies (e.g. trastuzumab, pertuzumab, bevacizumab, rituximab), cancer growth blockers (e.g. Tyrosine kinase inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors, Histone deacetylase inhibitors, Hedgehog pathway blockers, BRAF and MEK inhibitors), anti angiogenics (e.g. aflibercept, ramucirumab, sunitinib, sorafenib, axitinib, regorafenib, cabozantinib), PARP inhibitors (e.g. Olaparib, rucaparib, niraparib) and mixtures thereof. The drug may be soluble in the fluid (e.g. the IV fluid) at the elevated temperature. Thus, the drug and the fluid (e.g. the IV fluid) may be delivered as a solution to the patient, which increases the uniformity of drug delivery. The drug may be insoluble in the fluid (e.g. the IV fluid) at the elevated temperature. The drug and the fluid may be delivered to a patient as a composition (e.g. a homogenous composition). This is typical for target drug delivery since the drug will be protected (e.g. by the drug carrier) to release effectively only at the location in the patient’s body that requires the treatment. ‘Soluble’, ‘insoluble’, and ‘elevated temperature’ are as described hereinbefore.

The apparatus is an apparatus for releasing a drug, comprising the heat exchanger unit as described herein. The apparatus optionally comprises the drug, wherein the drug carrier is loaded with said drug. The drug may operably egress the heat exchanger unit (via the outlet) as loaded in a drug carrier, or as a naked drug (e.g. without the drug carrier).

The apparatus may be an apparatus for delivering a drug and a fluid (e.g. an IV fluid), preferably simultaneously. The apparatus may be an apparatus for warming the fluid (e.g. the IV fluid) and the drug carrier, preferably simultaneously. The apparatus optionally comprises the heating unit, as described herein.

After or during manufacturing, the apparatus (including its optional component parts) may be suitably sterilised. Thus, the apparatus is a sterilised apparatus. Sterilization may kill the microorganisms that would otherwise pose a health risk to the practitioners and patients. The apparatus may be provided within a packaging. The packaging may be a sterilised packaging. It may be that the present invention provides a product comprising the apparatus (e.g. the sterilised apparatus) as described herein within the packaging (e.g. the sterilised packaging). The product preferably comprises instructions for use. The instructions may contain information for preparing the apparatus for use in accordance with the methods described hereinafter. The instructions may be supplied in the form of a label, a booklet, a brochure, a leaflet, or in any medium capable of storing the information and communicating it to a practitioner.

The present invention extends to a method of making the apparatus as described herein, comprising providing a heat exchanger unit (excluding the drug carrier) as described herein, and treating said unit with a drug carrier capable of releasing a drug to thereby provide the drug carrier, wherein optionally, the drug carrier is loaded with a drug. The method may comprise treating the at least one surface of the internal fluid passageway with the drug carrier. Herein, treating may refer to bonding (e.g. mechanically affixing, adhering) the drug carrier to said surface. The method may comprise adhering the drug carrier to said surface via a linker (e.g. an adhesive). After treating, the method may comprise loading the drug carrier with a drug. The drug and the drug carrier are as described herein. The method may comprise sterilising the apparatus, preferably after treating the heat exchanger unit with the drug carrier. The method may further comprise placing the apparatus into a sterilised packaging. A heating means may be separately made, provided, and packed.

Further, the present invention extends to a method of operating an apparatus or preparing an apparatus for use, comprising providing an apparatus as described herein and providing a fluid preferably an intravenous fluid to the fluid passageway of said apparatus. The drug carrier may be loaded with a drug. If not, the method comprises a step of loading the drug carrier with a drug. The method may comprise attaching the drug-loaded heat exchanger unit to the heating unit. The method may comprise connecting the drug loaded heat exchanger unit to a fluid conduit via the inlet and the outlet. The heat exchanger unit, the drug, the drug carrier, the heating unit, and the fluid conduit are as described herein.

The present invention also extends to a method of activating a drug carrier to release a drug, comprising: providing an apparatus as described herein; and activating the drug carrier to release a drug by (i) providing a fluid, preferably an intravenous fluid, to the fluid passageway of said apparatus, and/or (ii) transferring heat to the fluid passageway of said apparatus via the heat transfer surface. The fluid may be an IV fluid, typically blood, blood plasma, or saline. The fluid may be a saline. The heat may be provided by a heating unit. If the drug carrier in the apparatus is not loaded with a drug, the method further comprises a step of loading the drug carrier with a drug before activating said carrier. The heat exchanger unit, the drug, the drug carrier and the heating unit are as described herein. The internal fluid passageway may be provided with the drug carrier. The drug carrier may be in thermal communication with (and in fluid communication with) said passageway. The method may comprise transferring heat to the fluid passageway via the heat transfer surface, to heat the drug carrier. Optionally and concurrently, the method may comprise transferring heat to the fluid passageway via the heat transfer surface, to heat the provided fluid (preferably an intravenous fluid). The method may be a method of warming the drug carrier and/or the fluid (e.g. IV fluid), typically a method of warming the drug carrier and the fluid (e.g. IV fluid) simultaneously.

Description of the Drawings

The present invention will now be illustrated with reference to the following non-limiting figures, in which:

Figure 1 is a schematic view of the apparatus according to an embodiment of the present invention;

Figure 2 is a schematic view showing different layers of materials forming part of the heat exchanger unit shown in Figure 1 ;

Figures 3, 4 and 5 are illustrations of the heat exchanger unit of Figure 2;

Figure 6 is a photo of an assembled apparatus according to an embodiment of the present invention;

Figure 7 is a flow chart of a method of making the heat exchanger unit according to an embodiment of the present invention; and

Figure 8 is a flow chart of a method of preparing the heat exchanger unit for use according to an embodiment of the present invention.

In the drawings, like parts are denoted by like reference numerals.

In detail, figure 1 shows an apparatus including a heat exchanger unit 1 and a heater unit 2. The heat exchanger unit 1 includes an inlet 4 and an outlet 5 for attachment to a first IV line 3 and second IV line 6 respectively. An appropriate valve or seal (not shown) is provided on the inlet 4 and outlet 5. The heat exchanger unit 1 is in the form of a disposable cassette, removably attachable to the heating unit 2. This can reduce the costs and allow the expensive heating unit 2 to be reused. In other embodiments, a second, separate heat exchanger unit may be provided so that the heat exchanger unit 1 may fit into that second unit. Then the second heat exchanger unit is removably attached to the heating unit 2. This can improve the hygiene of the apparatus.

Figure 2 shows different layers of material forming a part of the heat exchanger unit 1 in detail. The figure is not to scale and is at least exaggerated on the vertical and horizontal axes. In the figure, the surface of the heat exchanger unit operably coupled to the heating unit is comprised in a parylene layer 7. Suitable alternatives to parylene may also be used. Parylene layer 7 is provided with a relatively thick layer 8 (for structural stiffness) of aluminium, which is provided with another parylene layer 9. Any of the materials mentioned above may of course be replaced by any suitable alternative having appropriate thermal or electrical conductivity, structural stiffness and/or suitability for use in a medical or other setting. Although a three-layered structure is shown, it is understood that other structures (e.g. single parylene layer, single aluminium layer, parylene layer coated with aluminium layer) may also be contemplated. In figure 2, the parlyene layer 9 is provided with a layer of adhesive 10 (e.g. glue). A layer formed of nanoporous anodic alumina (NAA) 11 is adhered to the parylene layer 9 via the adhesive 10 (e.g. glue). The NAA layer 11 is exaggerated on scale for the sake of visual representation. This nanoporous NAA layer 11 has a plurality of pores, each represents a substantially II shape. The NAA 11 is a suitable drug carrier. The NAA 11 is bonded (via adhesive 10) to the layer 9, but other ways of providing a drug carrier may also be contemplated. For example, the drug carrier may comprise (e.g. be) a hydrogel adhered to layer 9. It will be understood that the adhesive (e.g. glue) is an optional ingredient. It may be that the hydrogel is self-adhered to layer 9 directly (e.g. when the hydrogel is a sticky hydrogel). In the figure, NAA 11 is further provided with a second drug carrier 12 which is a multiple layer polyelectrolyte. The drug 13 is in contact with the second drug carrier 11. It is also possible for the drug 13 to be directly loaded to NAA 11 , for example, to these substantially U-shaped pores. Although a drug 13 is shown, it is understood that drug 13 is an optional feature of the invention. A single drug carrier such as NAA 11 or hydrogel may also be used instead of a plurality of drug carriers 11 , 12. The NAA layer 11 , the multiple layer polyelectrolyte 12 and the drug 13 are all exaggerated on scale for the sake of visual representation.

Figures 3, 4 and 5 are illustrations (not to scale or necessarily complete or accurate in every detail) of the heat exchanger unit 1 of Figure 2. Figure 3 is a top view. Figure 4 is a cross sectional view at X-X’. Figure 5 is a bottom view. The heat exchanger unit 1 is provided in the form of a disposable cassette of mostly plastic construction (for sufficient rigidity at relatively low cost and little weight) with the bottom portion having a construction essentially as described above in relation to Figure 2. An inlet 4 and outlet 5 connector are shown, having a corresponding inlet portion 14 and outlet portion 15 of the fluid channel where it first makes relatively good thermal contact with the heater element of the heating unit 2 (not shown). Sealing elements are provided, cooperating also with a plastic support structure 16, to ensure that the fluid channel 17 and the above-described layers of parylene and aluminium remain well-bonded and in good thermal contact. At the base of the heat exchanger unit 1 there is provided a uniform flat surface 18 for making a good thermal contact with the heater unit 2 (not shown). Interlocking vertical plastic webs 19 provide additional rigidity and strength.

Figure 6 is a photo of an assembled apparatus (A) including a heating unit 2, a heat exchanger unit 1 and a second heat exchanger unit 20. The heating unit 2 has a docking cradle 21 to hold the second heat exchanger unit 20. The heat exchanger unit 1 is shown mounted within the second heater exchanger unit 20, and the unit 20 is shown mounted within the docking cradle 21 , in turn. In addition, two IV lines 3, 6 are shown (partially) to demonstrate the use of the apparatus. The heat exchanger unit 1 is a disposable cassette with features essentially the same as described in figures 2 - 5.

Figure 7 shows a flow chart of a method of making the heat exchanger unit according to an embodiment of the present invention. In step 701 , a heat exchanger unit without drug carrier is provided. In step 702, a drug carrier loaded with a drug is provided. The heat exchanger unit provides a surface defining an internal fluid passageway. A layer of adhesive (e.g. glue) is applied to at least part of or substantially all of that surface (step 703). Preferably, the layer of adhesive (e.g. glue) is applied to the part of the surface that is adjacent to a heating unit when the apparatus is in use. Additionally or alternatively, a layer of adhesive (e.g. glue) can be applied to the drug carrier loaded with the drug. Said drug carrier may be provided in the form of a layer and the adhesive (e.g. glue) may be applied to that layer. The drug carrier may be a hydrogel and the adhesive (e.g. glue) may be provided to (e.g. comprised in) the hydrogel. As explained hereinbefore, the adhesive (e.g. glue) is optional. The drug carrier may be bonded (e.g. adhered) to the surface of the heat exchanger unit by other means. By way of example, a suitable sticky hydrogel may adhere to said surface without the use of an adhesive (e.g. glue). In step 704, the drug carrier is adhered to the surface of the internal fluid passageway. In this way, the heat exchanger unit is formed. Although in this flowchart, the drug carrier is pre-loaded with a drug before adhering to the surface of the internal fluid passageway, it is also possible to load the drug after the drug carrier has been adhered to said surface. Alternatively, the drug carrier is free from a drug. The drug can be loaded immediately before the apparatus is in use. Apart from adhering, other suitable mechanisms of providing the drug carrier to the internal fluid passageway may also be used such as mechanically affixing the drug carrier layer to the surface of the fluid passageway. In step 705, the heat exchanger unit containing the drug carrier is properly sterilised. In step 706, the sterilised unit is packed within a packaging. In this way, a product comprising a packaging within which a clean unit is contained is finalised.

Figure 8 shows a flow chart of a method of preparing the heat exchanger unit for use according to an embodiment of the present invention. This method can also be a method of operating the heat exchanger unit. In step 801 , an apparatus comprising a heat exchanger unit is provided. Said unit also comprises a drug carrier. In step 802, one or more drugs are loaded to the drug carrier. If the drug carrier comprised in the heat exchanger unit has already been loaded with a drug, step 802 is not necessary. In step 803, an intravenous fluid (IVF) is loaded into the fluid passageway of the heat exchanger unit. Then, the heat exchanger unit is attached to a heating means (step 804). A second heat exchanger unit may also be used. If so, after loading the IVF, the heat exchanger unit comprising the drug carrier is attached to (e.g. mounted to) the second heat exchanger unit first. Then, the second heat exchanger unit is attached to (e.g. mounted to) the heating means.

Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to and do not exclude other components, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. Features, integers, characteristics, or groups described in conjunction with a particular aspect, embodiment, or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. Numerical ranges expressed in the format ‘from x to y’ and ‘between x and y’ are understood to include x and y, unless specified otherwise. When for a specific feature multiple optional ranges are described, it is understood that all ranges combining the different endpoints are also contemplated. Except in the operating and comparative examples, or where otherwise explicitly indicated, all numbers in this description indicating amounts of material or conditions of reaction, physical properties or materials and/or use are to be understood as modified by the word ‘about’.

Claims

1. An apparatus for releasing a drug, comprising: (i) a heat exchanger unit comprising an inlet, an outlet, an internal fluid passageway connecting the inlet and the outlet, and a heat transfer surface configured to transfer heat to the internal fluid passageway, and (ii) a drug carrier capable of releasing a drug, wherein the drug carrier is in communication with the internal fluid passageway.

2. An apparatus according to claim 1, wherein the internal fluid passageway is provided with the drug carrier and the heat transfer surface is for transferring heat to the drug carrier.

3. An apparatus according to claim 1 or claim 2, wherein the drug carrier and the internal fluid passageway are in thermal communication, the heat transfer surface being configured to transfer heat to said passageway so as to heat said drug carrier.

4. An apparatus according to any one of the preceding claims, wherein the apparatus further comprises a heating unit configured to heat the heat exchanger unit via the heat transfer surface, and the heat exchanger unit is removably attachable to the heating unit.

5. An apparatus according to any one of the preceding claims, wherein the fluid is an intravenous fluid (IVF).

6. An apparatus according to any one of the preceding claims, wherein the apparatus is for delivering the drug to a patient, preferably for delivering the drug and the fluid simultaneously to the patient.

7. An apparatus according to any one of the preceding claims, wherein the heat exchanger unit provides at least one surface defining the internal fluid passageway, and the drug carrier is bonded to the at least one surface of said passageway.

8. An apparatus according to claim 7, wherein the drug carrier is bonded to the at least one surface of the internal fluid passageway and the at least one surface is an internal surface of a side of the heat exchanger unit, and the heat transfer surface is at least part of an external surface of the same side of the heat exchanger unit.

9. An apparatus according to claim 7 or claim 8, wherein the heat exchanger unit comprises a first parylene layer comprising the heat transfer surface, an aluminium layer, and a second parylene layer such that the first parylene layer is provided with the aluminium layer and the aluminium layer is provided with the second parylene layer, a surface of the second parylene layer defining at least part of the internal fluid passageway to which the drug carrier is bonded.

10. An apparatus according to any one of claims 7 to 9, wherein the drug carrier is bonded to the internal fluid passageway via adhesion.

11. An apparatus according to any one of the preceding claims, wherein the drug carrier is selected from hydrogels, lamellae, membranes, vesicles, micelles, bilayers, liposomes, capsules, dendrimers, polymers, microspheres, matrices, filaments, quantum dots, nanostructures, and mixtures thereof, preferably selected from hydrogels, nanostructures and mixtures thereof.

12. An apparatus according to claim 11, wherein the drug carrier is a nanostructure preferably a porous nanostructure, comprising one or more of the followings: polyvinyl alcohol, polytetrafluoroethylene, polylactic acid, polyethylene glycol, poly(lactic-co- glycolic acid), poly(caprolactone), synthetic polymers, hydrophilic polymers, peptides, alginate, chitosan, chitin, glycosaminoglycans, hyaluronic acid, collagen, gellan gum, starch, guar gum, gum Arabic, galactans, carrageenan, Xanthan gum, cellulose, hydroxyapatite, silicone, gluconate, sucrose, dextran, octocalciumphosphate, dicyclopentadiene, nanoporous anodic alumina, and polyelectrolyte.

13. An apparatus according to claim 12, wherein the drug carrier comprises nanoporous anodic alumina (NAA) and wherein optionally the nanopores of the NAA are configured to be loaded with a drug or a further drug carrier.

14. An apparatus according to claim 13, wherein the drug carrier comprising nanoporous anodic alumina (NAA) is a first drug carrier, the apparatus further comprises a second drug carrier which comprises one or more electrolytes in the form of multilayers, and the first drug carrier is provided with the second drug carrier and wherein optionally, the nanopores of the NAA are loaded with the second drug carrier.

15. An apparatus according to any one of the preceding claims, wherein the drug carrier is designed to be activated to release a drug by one or more of the following factors: light, sound, heat, magnetism, pH, ionic strength, hydrolysis, enzymes, intravenous fluid, osmosis, diffusion, elution, humidity, preferably by heat and/or by intravenous fluid.

16. An apparatus according to any one of the preceding claims, wherein the drug carrier is loaded with a drug.

17. An apparatus according to claim 16, wherein the drug is compatible with the fluid and the drug is selected from therapeutic drugs, prophylactic drugs, diagnostic drugs, and mixtures thereof.

18. A method of making the apparatus according to any one of the claims 1 to 17, comprising: (i) providing a heat exchanger unit as described in any one of the claims 1 to 10, excluding the drug carrier; and (ii) treating the internal fluid passageway with a drug carrier capable of releasing a drug to thereby provide the drug carrier.

19. A method of operating an apparatus or preparing an apparatus for use, comprising: providing an apparatus according to any one of the claims 1 to 17; providing a fluid, preferably an intravenous fluid, to the fluid passageway of said apparatus, wherein the drug carrier of the apparatus is either loaded with a drug, or the method further comprises loading the drug carrier with a drug.

20. A method of activating a drug carrier to release a drug, comprising: providing an apparatus according to any one of the claims 1 to 17; and activating the drug carrier to release a drug by (i) providing a fluid, preferably an intravenous fluid, to the fluid passageway of said apparatus, and/or (ii) transferring heat to the fluid passageway of said apparatus via the heat transfer surface, wherein if the drug carrier in the apparatus is not loaded with a drug, the method further comprises a step of loading the drug carrier with a drug before activating said carrier.